Fibrinogen Aα Thr312Ala polymorphism specifically contributes to chronic thromboembolic pulmonary hypertension by increasing fibrin resistance

PLoS One. 2013 Jul 22;8(7):e69635. doi: 10.1371/journal.pone.0069635. Print 2013.

Abstract

Background: Polymorphisms are associated with chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary thromboembolism (PTE), but no polymorphism specific to CTEPH but not PTE has yet been reported. Fibrin resistance is associated with CTEPH, but the mechanism has not been elucidated.

Methods: Polymorphisms were analyzed in 101 CTEPH subjects, 102 PTE subjects and 108 healthy controls by Massarray or restriction fragment length polymorphism (RFLP). Plasmin-mediated cleavage of fibrin was characterized in 69 subjects (29 with CTEPH, 21 with PTE and 19 controls).

Results: Genotype frequencies and allele frequencies of fibrinogen Aα Thr312Ala were significantly higher in CTEPH subjects than in controls and PTE subjects, while there was no difference between PTE subjects and controls. The odd ratio (OR 2.037) and 95% confidence interval (95% CI, 1.262-3.289) showed that Thr312Ala polymorphism was a risk factor for CTEPH but not PTE. Fibrin from CTEPH subjects was more resistant to lysis than that from PTE subjects and controls. Fibrin resistance was significantly different between Aα Thr312Ala (A/G) genotypes within CTEPH subjects, and the fibrin with GG genotype was more resistant than that with AA and AG genotype.

Conclusions: Fibrinogen Aα Thr312Ala (A/G) polymorphism was associated with CTEPH, but not PTE, suggesting that the fibrinogen Aα Thr312Ala polymorphism may act as a potential biomarker in identifying CTEPH from PTE. GG genotype polymorphism contributes to CTEPH through increasing fibrin resistance, implying that PTE subjects with fibrinogen Aα GG genotype may need long-term anticoagulation therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Chronic Disease
  • Female
  • Fibrin / metabolism*
  • Fibrinogen / genetics*
  • Fibrinolysis / genetics*
  • Gene Frequency
  • Genotype
  • Humans
  • Hypertension, Pulmonary / complications
  • Hypertension, Pulmonary / genetics*
  • Hypertension, Pulmonary / physiopathology*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Pulmonary Embolism / complications*
  • Young Adult

Substances

  • fibrinogen Aalpha
  • Fibrin
  • Fibrinogen

Grant support

This work was supported by the following funds: Fund of China 973 program (2009CB522107), National Natural Science Foundation of China (81228001, 81070042, 81111130212, 81200041) and Fund of PVRI (2011). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.